New drugs are available to treat graft-versus-host disease (GVHD). Combined with early detection and advances in understanding the underlying mechanisms of the disease, it may be possible to reduce the morbidity and mortality of this major complication of allogeneic transplantation.
The risk of grade II-IV acute GVHD after allogeneic related transplants has decreased from 45% in 1976 to under 30% in 2001. Importantly, the majority of this decrease has been in the most severe manifestations (grades III-IV). [1]
Acute GVHD usually occurs before day 100 post-transplant. Chronic GVHD has somewhat different presentation and often occurs later.
Prevention of acute GVHD
Several successful strategies are being used to reduce the risk of developing acute GVHD. These include:
Prophylaxis with immunosuppressive drugs
Selective depletion of alloreactive T lymphocytes from the donor graft
Using umbilical cord blood as the source of donor cells
Intensive prophylaxis with immunosuppressive drugs is standard practice for all patients undergoing allogeneic transplantation. Standard drugs in use include cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil, corticosteroids or antithymocyte globulin (ATG). The decrease in the incidence and severity of acute GVHD is in large part due to the widespread prophylactic use of these drugs, particularly cyclosporine and methotrexate.
New combinations including sirolimus might even be more effective. A 2007 report of 83 transplants showed good outcomes when using sirolimus and tacrolimus, without methotrexate, as prophylaxis for acute GVHD. The incidence of grade II-IV and III-IV acute GVHD in this study were 20.5% and 4.8%, respectively, and there were only two deaths (2.4%) due to GVHD. [2]
A randomized prospective study of 109 transplant patients demonstrated that patients receiving pre-transplant antithymocyte globulin (ATG) experience significantly less chronic GVHD than patients who did not receive ATG. After a median follow up of 5.7 years, 60% of non-ATG patients experienced chronic GVHD compared to 37% of patients who received ATG (p=0.05). Extensive chronic GVHD was present in 41% of non-ATG patients and in 15% of ATG patients (p=0.01). [3] See Advances in Conditioning Regimens for more information.
Selective depletion of alloreactive T lymphocytes from the donor graft
GVHD is a manifestation of alloreactive donor T cells acting against the patient. Depleting donor T cells prior to infusion into the patient is an effective method of reducing the risk of developing GVHD. However, doing so raises the risk of graft failure, infection and relapse. In addition, T-cell depletion can reduce the beneficial graft-versus-malignancy effect that can act to eradicate residual disease in the patient. Newer techniques to selectively deplete only alloactivated donor T cells from donor grafts are being tested.
Using umbilical cord blood as the source of donor cells
Because of the immunological immaturity of the T cells in umbilical cord blood, transplants using this source of cells have a reduced incidence and severity of GVHD. [4,5] Although more commonly used in pediatric patients, cord blood transplantation has been successfully used in adults when sufficient nucleated cell doses are used. [5,6,7] See Hematopoietic Cell Sources Tailored to the Patient for more information.
Closer HLA matching between donor and patient
DNA-based tissue typing has increased the accuracy and specificity of HLA typing, which allows for more precise HLA matching between donors and transplant patients. Because the alloreaction of donor T cells against the patient's cells is reduced as the degree of HLA match is increased, closer HLA matching can significantly reduce the risks of GVHD. [8]
Treatment of acute GVHD
If acute GVHD does develop after transplantation, immunosuppressive drugs are administered, typically corticosteroids along with cyclosporine or tacrolimus. Satisfactory responses to this steroid treatment are observed in only 50% of patients. New drugs and new strategies are also available that can supplement standard treatment, including:
Monoclonal antibodies (e.g., anti-CD3, -CD5, and -IL-2 antibodies)
Mycophenolate mofetil
Alemtuzumab (Campath)
Antithymocyte globulin (ATG)
Sirolimus
Treatment of chronic GVHD
Primary therapy for chronic GVHD is administration of steroids, usually cyclosporine and prednisone. Clinical trials investigating treatments of steroid-refractory chronic GVHD using the following drugs have reported success rates of between 25% and 50%:
Tacrolimus
Mycophenolate mofetil
Antithymocyte globulin (ATG)
Thalidomide
Daclizumab
Extracorporeal photopheresis
Infliximab
Clofazimine [9,10]
In 2006, a National Institutes of Health (NIH) Consensus Conference established guidelines for diagnosis, ancillary therapy and supportive care in chronic GVHD. The Conference reports outlined proposed treatments for symptoms and gives recommendations for patient education, preventive measures, and appropriate follow-up. Also developed were standard criteria for the diagnosis of chronic GVHD and a proposed new clinical scoring system that describes the extent and severity of chronic GVHD for each organ or site.
In all, six consensus documents were produced, and they are excellent resources for physicians wishing to learn more about chronic GVHD. [11-16]
References
Horowitz MM. Uses and growth of hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation, 3rd ed. Malden, Mass: Blackwell, 2004:9-15.
Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007; 109(7):3108-3114. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/109/7/3108
Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: Long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006; 12(5):560-565. http://www.bbmt.org/article/PIIS1083879105014163/fulltext
Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001; 344(24):1815-1822. http://content.nejm.org/cgi/content/abstract/344/24/1815
Brunstein CG, Barker JN, Weisdorf DJ et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007; 110(8):3064-3070. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/110/8/3064
Morishima Y, Sasazuki T, Inoko H. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002; 99(11):4200-4206. http://www.bloodjournal.org/cgi/content/full/99/11/4200
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005; 11(12):945-956. http://www.bbmt.org/article/PIIS1083879105006312/abstract
Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant. 2006; 12(1):31-47. http://www.bbmt.org/article/PIIS1083879105007226/abstract
Schultz KR, Miklos DB, Fowler D, et al. Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker Working Group Report. Biol Blood Marrow Transplant. 2006; 12(2):136-137. http://www.bbmt.org/article/PIIS1083879105007834/abstract
Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12(3):252-266. http://www.bbmt.org/article/PIIS108387910600070X/abstract
Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006; 12(4):375-396. http://www.bbmt.org/article/PIIS1083879106001613/fulltext
Martin PJ, Weisdorf D, Przepiorka D, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. Design of Clinical Trials Working Group report. Biol Blood Marrow Transplant. 2006;12(5):491-505. http://www.bbmt.org/article/PIIS1083879106002503/abstract
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